Bendamustine, 4-[5-[Bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid, is used in the treatment of leukemia and certain lymphomas. However, this compound has limited chemical stability in plasma, thereby requiring high or repeated doses in order to achieve a therapeutic effect. United States Patent Application Publication No. 2006/0159713 (Brittain et al.) indicates that, once reconstituted into aqueous solutions, bendamustine quickly degrades and must therefore be administered to patients as quickly as possible. Maas et al.; “Stabililitat von Bendamustinhydrochlorid in Infusionslosungen”; Pharmazie 49:775-7 (1994) discloses that bendamustine hydrochloride is stable for only 9 hours at 23° C. in saline solution.
Attempts have been made to increase the stability of bendamustine by complexing such molecule with polymeric materials. However, the approaches taken thus far have only achieved marginal success. Pencheva et al; “HPLC study on the stability of bendamustine hydrochloride immobilized onto polyphosphoesters; J. Pharma. Biomed. Anal; (2008) attempted to improve the stability of bendamustine by complexing such compound with polyphosphoesters. However, FIG. 2 of such article shows that even the most stable complex decreases by a full log point (90%) in about 45 minutes at pH 7.
Evjen; “Development of Improved Bendamustin-Liposomes”; Masters Thesis; University of Tromso (2007) employed dual asymmetric centrifugation to incorporate bendamustine into liposomes. According to Table 18 (on page 79), these formulations only provide a marginal increase of stability relative to free bendamustine (20 minutes half-life vs. 14 minutes half-life for free bendamustine).
Accordingly, there is a need for improved formulations of bendamustine which will provide enhanced stability in aqueous solutions.